Simultaneous deletion of MyD88 and Trif delays major histocompatibility and minor antigen mismatch allograft rejection

Abstract

This study investigated whether ablation of all Toll-like receptor (TLR) signaling influenced skin allograft rejection across a complete donor/recipient mismatch of major histocompatibility and minor antigens. We predicted that defective TLR signaling would interfere with the activation of donor dendritic cells (DC) in vivo, by preventing DC activation in response to local environmental ("danger") signals. The ablation of TLR signals would therefore be associated with decreased activation of host T cells and decreased graft rejection. Using mice with deletions of the proximal TLR adapter proteins MyD88 or Trif, and those with simultaneous deletions of both MyD88 and Trif, we demonstrated that absence of both MyD88 and Trif adapter proteins prolonged skin graft survival, notably across a complete MHC and minor antigen barrier. Absence of MyD88 or Trif alone only had a modest effect on graft survival across even a minor MHC antigen difference. Prolonged survival of skin grafts from mice deficient in both MyD88 and Trif was associated with diminished migration of donor cells to draining lymph nodes and, subsequently, with delayed infiltration of host T cells into the grafted tissue.

To the Editor

“…This finding is in agreement with those of Mckay et al [1] who noted a delay in transplant rejection when MyD88 was absent from donor skin transplants. As acknowledged by the authors, since MyD88 and Trif signaling was intact in recipients, one cannot be sure of the full impact of the dual deletion of Trif and MyD88 signaling during transplant rejection based on their work [1]. This is important since the indirect pathway is sufficient for allograft rejection [4].…”

“…In these studies we found that absence of MyD88 impaired the ability of mature DC to accumulate in the draining lymph nodes of transplants both in the minor HY incompatible and the fully MHC mismatched skin transplant model. These results are consistent with the data presented by Mckay et al [1]. In our unpublished findings, we have found that mice with defective Trif signaling (LPS2, the same mice used by Mckay et al [1]) manifest an intact ability to reject HY incompatible skin transplants.…”

“…These results are consistent with the data presented by Mckay et al [1]. In our unpublished findings, we have found that mice with defective Trif signaling (LPS2, the same mice used by Mckay et al [1]) manifest an intact ability to reject HY incompatible skin transplants. Furthermore, we have noted that absence of MyD88 completely abrogates the ability to reject HY incompatible skin transplants using MyD88 deficient mice that are backcrossed onto the C57BL/6 background.…”

“…Yet rejection occurred in every case, although with delayed kinetics, if MyD88 signaling was present in either the donor or recipient [2]. This finding is in agreement with those of Mckay et al [1] who noted a delay in transplant rejection when MyD88 was absent from donor skin transplants. As acknowledged by the authors, since MyD88 and Trif signaling was intact in recipients, one cannot be sure of the full impact of the dual deletion of Trif and MyD88 signaling during transplant rejection based on their work [1].…”

“…We were interested in the recent article investigating the role of Trif and MyD88 signaling within donor allografts [1]. In contrast to the authors' conclusions, we found that the work agrees with our prior reports both in a minor mismatched skin transplant model and in the setting of fully MHC mismatched skin or cardiac transplant rejection [2,3].…”